Technical advances in the identification, cloning, expression, and manipulation of nucleic acid molecules and the deciphering of the human genome have greatly accelerated the discovery of novel therapeutics. Rapid nucleic acid sequencing techniques can now generate sequence information at unprecedented rates and, coupled with computational analyses, allow the assembly of overlapping sequences into partial and entire genomes and the identification of polypeptide-encoding regions. A comparison of a predicted amino acid sequence against a database compilation of known amino acid sequences allows one to determine the extent of homology to previously identified sequences and/or structural landmarks. The cloning and expression of a polypeptide-encoding region of a nucleic acid molecule provides a polypeptide product for structural and functional analyses. The manipulation of nucleic acid molecules and encoded polypeptides may confer advantageous properties on a product for use as a therapeutic.
In spite of the significant technical advances in genome research over the past decade, the potential for the development of novel therapeutics based on the human genome is still largely unrealized. Many genes encoding potentially beneficial polypeptide therapeutics or those encoding polypeptides, which may act as “targets” for therapeutic molecules, have still not been identified. Accordingly, it is an object of the invention to identify novel polypeptides, and nucleic acid molecules encoding the same, which have diagnostic or therapeutic benefit.
The isolation of nucleic acid sequences encoding tumor necrosis factors (TNFs) α and β led to the identification of a superfamily of TNF cytokines that includes fas ligand (FasL), CD27 ligand (CD27L), CD30 ligand (CD30L), CD40 ligand (CD40L), TNF-related apoptosis-inducing ligand (TRAIL, also designated as AGP-1), osteoprotegerin binding protein (OPG-BP or OPG ligand), 4-1BB ligand, LIGHT, APRIL, and TALL-1 (also designated as BAFF, THANK, BlyS, and zTNF4). See Smith et al., 1994, Cell 76:959-62; Lacey et al., 1998, Cell 93:165-76; Chichepotiche et al., 1997, J. Biol. Chem. 272:32401-10; Mauri et al., 1998, Immunity 8:21-30; Hahne et al., 1998, J. Exp. Med. 188:1185-90; Shu et al., 1999, J. Leukocyte Biology 65:680-83. The members of this ligand family are unified by their structure, particularly at the C-terminus, and expression in immune compartments (Smith et al., 1994). Furthermore, with the exception of LT-α, all of the members of this family are type II transmembrane proteins, characterized by a conserved 150 amino acid region within the C-terminal extracellular domain, which folds into a characteristic β-pleated sheet sandwich and trimerizes. This conserved region can be proteolyticaly released, thus generating a soluble functional form (Banner et al., 1993, Cell 73:431-45).
Many members within this ligand family are expressed in lymphoid enriched tissues and play important roles in the immune system development and modulation (Smith et al., 1994). For example, TNFα, which is mainly synthesized by macrophages, has been shown to be an important mediator for inflammatory responses and immune defenses (Tracey and Cerami, 1994, Annu. Rev. Med. 45:491-503). Fas-L, which is predominantly expressed in activated T cells, has been shown to modulate TCR-mediated apoptosis in thymocytes (Nagata and Suda, 1995, Immunology Today 16:39-43; Castrim et al., 1996, Immunity 5:617-27). CD40L, which is also expressed in activated T cells, provides an essential signal for B cell survival, proliferation, and immunoglobulin isotype switching (Noelle, 1996, Immunity 4:415-19).
The cognate receptors for most of the TNF ligand family members have been identified. These receptors share characteristic multiple cysteine-rich repeats within their extracellular domains, and do not possess catalytic motifs within cytoplasmic regions (Smith et al., 1994). The receptors signal through direct interactions with death domain proteins (e.g., TRADD, FADD, and RIP) or with the TRAF proteins (e.g., TRAF2, TRAF3, TRAF5, and TRAF6), triggering divergent and overlapping signaling pathways, e.g., apoptosis, NF-B activation, or JNK activation (Wallach et al., 1999, Ann. Rev. Immunol. 17: 331-67). These signaling events lead to cell death, proliferation, activation, or differentiation. The expression profile of each receptor member varies. For example, while TNFR1 is expressed in a broad spectrum of tissues and cell types, the cell surface receptor for OPGL is mainly restricted to the osteoclasts (Hsu et al., 1999, Proc. Natl. Acad. Sci. U.S.A. 96:3540-45).
The TNF family ligand TALL-1 is a type II transmembrane protein that is produced by cells of myeloid origin. TALL-1 is known to bind to two other members of the TNFR family: transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI) and B cell maturation antigen (BCMA). It is an object of the invention to identify nucleic acids encoding a receptor for TALL-1. Since TALL-1 is believed to play a role in inflammatory and immune processes, TALL-1R molecules would have wide application in the medical arts, particularly in treating autoimmune and inflammatory disorders.